Diethylenetriaminepentaacetic acid (DTPA) is a chelating agent. Chelating agents are used as standard in industry since they form stable complexes with metals, to some extent selectively. In the pharmaceutical industry, diethylenetriaminepentaacetic acid is used in the form of a calcium or zinc complex. These complexes are able to exchange the cation for another cation if this cation has a higher complex formation constant, i.e. forms a stable complex with the complexing agent. Solutions of these salts are used in Europe and in the USA for the complexation of radionuclides. (Ménétrier F, Grappin L, Raynaud P, Courtay C, Wood R, Joussineau S, List V, Stradling G N, Taylor D M, Bérard P, Morcillo M A & Rencova J (2005) Treatment of accidental intakes of plutonium and americium: Guidance notes. Appl Radiat Isot, 62: 829-846.)
Finished drug products with Zn-DTPA are registered under the trade names pentetate zinc trisodium (USA, NDA August 2004, hameln pharmaceuticals) and zinc trisodium pentetate (DE, Heyl Chemisch-pharmazeutische Fabrik GmbH & Co.).
The drug products are administered by intravenous injection. They are indicated for a nuclear incident in which radioactive heavy metals, such as plutonium, americium and curium have been released. Guilmette, R. A. et al “Effectiveness of continuously infused DTPA therapy in reducing the radiation dose from inhaled 244Cm203 aerosols” Health Physics, 1992. vol. 62, no. 4, pp. 311-318.
Efforts are also currently being undertaken to increase the oral bioavailability of the complex (WO 2007/145682).
For the intravenous dosage forms, the formation of the zinc complex in solution is a satisfactory synthetic route. However, the use for oral administration places higher demands on the physical properties of the active ingredient. The complex must be present in solid form. It should preferably be in a stable state that is easy to handle.
The synthesis of the active ingredient was first published in DE1223396 (Example 1). The standard method for preparing Zn-DTPA consists in providing an aqueous solution of pentasodium diethylenetriaminepentaacetate and the addition of zinc chloride or zinc oxide, according to the following scheme:

In this case, the isolation of the active ingredient is achieved via concentration of the reaction solution by distilling off the water and subsequent drying of the reaction product. The synthetic route presented in DE 1223396, however, leads to an amorphous product, which is very hygroscopic and accordingly difficult to grind.
In an application from Nanotherapeutics, the hygroscopy is also presented as a disadvantageous property of Zn-DTPA (WO 2007008480, Example 4). It is reported that the lyophilized powder, absorbs more than 10% by weight of water over 24 h. DE1223396 gives no indication of the existence of a crystalline form, or different polymorphic forms of Zn-DTPA.
Table 1 shows the hygroscopy of the solid when the product is obtained by the route known from the prior art by concentration of the reaction mixture (cf. also Example 1).
TABLE 1Time [h]Mean mass increase [%]No.124682448Batch 10.510.891.562.352.957.3811.92Batch 20.560.971.732.613.267.8212.02
The mass increase due to hygroscopy after 12 hours is about 7-8%, and the mass increase of the sample after 48 hours is about 12%. This is around the value known from the prior art for Zn-DTPA. The hygroscopy of conventional Zn-DTPA is so great that, with sufficiently long exposure to air humidity, it even deliquesces due to its hygroscopy.
Ca-DTPA forms a similar complex due to the comparable electron configuration of calcium (Ca: [Ar]4s2; Zn:[Ar] 3d10 4s2). However, the complex is distinctly more unstable due to the different atom radii. A comparison of the two complexes in terms of their chemical and physical properties is therefore problematic.
To prepare Ca-DTPA, a method is described in which an alcohol is added to a cold aqueous solution of the product in order to effect a precipitation (GB944020). A crystalline form of this complex is however also not described here.
It has not been possible to date to prepare Zn-DTPA in a form which leads to a stable product that can be processed to an oral pharmaceutical dosage form under atmospheric conditions.
Against this background, it was the object of the present invention to provide Zn-DTPA in a form which is more stable under atmospheric conditions than the form known and preparable to date. In particular, it was the object of the invention to retard and/or reduce the hygroscopy of Zn-DTPA. In addition, the DTPA according to the invention should preferably be suitable for oral pharmaceutical dosage forms.
This object is achieved by trisodium zinc diethylenetriaminepentaacetate (Zn-DTPA) in crystalline form.